Clinical Radiology 69 (2014) 619e623
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Clinical Radiology journal homepage: www.clinicalradiologyonline.net
The prognostic significance of MRI-detected extramural venous invasion in rectal carcinoma W.G. Bugg a, A.K. Andreou a, D. Biswas b, A.P. Toms a, S.M. Williams a, * a b
Department of Radiology, Norfolk and Norwich University Hospital NHS Foundation Trust, Norwich, UK Department of Oncology, Norfolk and Norwich University Hospital NHS Foundation Trust, Norwich, UK
art icl e i nformat ion Article history: Received 30 October 2013 Received in revised form 6 January 2014 Accepted 14 January 2014
AIM: To assess whether there is a significant difference in the incidence of patients with metastases of rectal carcinoma at 1 year follow-up between magnetic resonance imaging (MRI)-detected extramural venous invasion (EMVI) and those without. MATERIALS AND METHODS: A search of our institution’s cancer registry revealed 788 patients with rectal carcinoma between January 2007 and April 2012. Those who were initially staged using MRI and computed tomography (CT) chest/abdomen/pelvis, and followed-up with a CT chest/abdomen/pelvis examination at 1 year were included in this retrospective study. Patients with synchronous metastases were excluded, leaving a cohort of 202 cases. Two consultant radiologists reviewed all MRI images and gave a consensus opinion regarding EMVI grade and vessel size involved. All CT images were reviewed for metastases. Results were analysed using chi-squared and Fisher’s exact tests. RESULTS: There were 53 cases (26.2%) of EMVI-positive rectal carcinoma. Of the patients with EMVI, 24.5% developed metastases at 1 year follow-up, compared to 6.7% of those without. There is a significant difference in prognosis between those patients with and those without MRI-detected EMVI (c2 ¼ 12.29, p < 0$001). Those with EMVI have a 3.7 times increased relative risk of developing metachronous metastases within 1 year of diagnosis. CONCLUSION: MRI-detected EMVI-positive rectal carcinomas are associated with an increased risk of metachronous metastases within 1 year of diagnosis. Currently, EMVI status does not directly influence the initial management of rectal carcinoma. This available and potentially prognostic feature could be used to guide treatment pathways to increase diseasefree survival. Ó 2014 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
Introduction The local staging of rectal carcinoma with highresolution magnetic resonance imaging (MRI) has been shown to be accurate1 and reproducible.2 It enables preoperative planning of primary tumour resection or may indicate the need for neoadjuvant therapy. The aim of this
* Guarantor and correspondent: S.M. Williams, Norwich Radiology Academy, Cotman Centre, Colney Lane, Norwich, Norfolk NR4 7UB, UK. Tel.: þ44 01603 286143; fax: þ44 01603 286146. E-mail address: [email protected] (S.M. Williams).
detailed preoperative staging is to facilitate long-term disease-free survival. A systematic approach for the reporting of local-staging MRI for rectal cancer has been developed as a result of the work carried out by the MERCURY Study Group.3,4 This highlights the most important staging characteristics, including extramural venous invasion (EMVI), which is recognized as a poor prognostic feature.1 EMVI is defined histologically as the presence of tumour cells beyond the muscularis propria in an endotheliumlined vessel.4 It is possible to diagnose both intra- and extramural venous invasion associated with rectal carcinoma during histological examination of a surgical
0009-9260/$ e see front matter Ó 2014 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.crad.2014.01.010
620
W.G. Bugg et al. / Clinical Radiology 69 (2014) 619e623
specimen.5 However, MRI can only demonstrate EMVI.1 EMVI will only be present in locally advanced rectal tumours, of stage T3 or T4.6,7 The diagnostic capabilities of MRI with respect to EMVI are, therefore, limited to the more severe end of the disease spectrum. It is accepted that venous invasion by colorectal cancer allows tumour cells to embolize, via the portal circulation, resulting in distant metastases through haematogenous spread.5 The liver is most commonly affected.8,9 Histologically detected venous invasion of rectal carcinoma is associated with a higher incidence of metachronous local10 and distant10,11 metastases. It is also associated with poorer overall survival rates.12 The presence of MRI-detected EMVI is a poor prognostic feature of rectal carcinoma and is associated with an increased risk of synchronous metastases.13 To the authors’ knowledge, the association between MRI-detected EMVI and the development of metachronous metastases has not been described in the literature. It is suggested that the increased incidence of metachronous metastases associated with EMVI-positive rectal cancers is, in some part, due to the presence of micrometastases.14,15 These are impossible to diagnose with initial staging computed tomography (CT). The authors’ hypothesise that micrometastases, if present at the time of initial staging, should progress to detectable metastases at an early stage if left untreated. The aim of the present study was to assess whether there is a significant difference in the incidence of patients with metastases at 1 year follow-up between those with MRIdetected EMVI and those without.
Materials and methods Institutional ethics committee approval for this retrospective study was not required but the study was performed in accordance with the principles of the Declaration of Helsinki. A search of our single-hospital electronic cancer registry (Somerset Informatics Service) revealed 788 patients with a diagnosis of primary rectal carcinoma recorded between January 2007 and April 2012. Those patients who were initially investigated via MRI of the rectum and a CT examination of the chest, abdomen, and pelvis for both local and distant staging, and also followed up with a CT examination of the chest, abdomen, and pelvis at 1 year post-diagnosis were included in the study. Patients who were found to have synchronous metastases at initial staging were excluded from the study. There were 229 cases that met the study inclusion criteria; of these, 27 cases had synchronous metastases and were excluded. A cohort of 202 cases remained (male ¼ 123, female ¼ 79; median age 66 years, range 32e84). For all cases that met the inclusion and exclusion criteria, the initial staging MRI images of the rectum were reviewed on a high-resolution picture archiving and communication system (Fujifilm Synapse, Fuji Photo Film Co. Ltd, Tokyo, Japan) workstation (Eizo Radiforce RX320 monitors, Eizo Corporation, Hakusan, Ishikawa, Japan) by two consultant
radiologists with a subspecialty interest in colorectal imaging (individual experience of 15 and 5 years, respectively). The MRI examinations were carried out using a 1.5 T Siemens Avanto (Siemens Medical Systems, Erlangen, Germany) system, using a six-channel body matrix coil anteriorly and a six-channel spine matrix coil posteriorly, which combine to create a 12-channel configuration. The standard imaging sequences obtained were axial T1-weighted turbo spin-echo [13 ms echo time (TE), 579 ms repetition time (TR), 320 256 matrix, 34 37 cm field of view (FOV), 6 mm section thickness, 8 mm spacing] and axial T2weighted turbo spin-echo (96 ms TE, 4960 ms TR, 320 256 matrix, 34 37 cm FOV, 6 mm section thickness, 8 mm spacing) of the pelvis. High-resolution sagittal T2weighted turbo spin-echo (97 ms TE, 4692 ms TR, 288 384 matrix, 23 25.1 cm FOV, 4 mm section thickness, 5 mm spacing), coronal oblique T2-weighted turbo spin-echo (81 ms TE, 4670 ms TR, 256 256 matrix, 22 24 cm FOV, 3 mm section thickness, 3.6 mm spacing) and axial oblique T2-weighted turbo spin-echo (81 ms TE, 5610 ms TR, 256 256 matrix, 22 24 cm FOV, 3 mm section thickness, 3.6 mm spacing) images were obtained of the rectal tumour. The reporters were blind to the study history and original report. The EMVI status of each case was assessed only. All cases of EMVI-positive disease were graded16 and the size of vessel involved was recorded. A consensus opinion was recorded for each study. The EMVI grading score used in this study was taken from the system proposed by Smith et al.16 Grades 0e2 are effectively EMVI-negative disease and were recorded as such, without distinction. Grades 3 and 4 correspond to EMVI-positive disease. Grade 3 EMVI describes tumour within a vein that does not alter its contour and may only slightly expand the vessel (Fig 1). Grade 4 EMVI describes an irregular expanded vein implying vessel wall invasion (Fig 4). The distance by which the EMVI had extended from the rectal tumour was assessed with respect to the size of vessel
Figure 1 Small vessel grade 3 EMVI (arrow) on coronal oblique T2weighted MRI. The involved vein is of intermediate signal (similar to the tumour and with no flow void), runs perpendicular to the rectal lumen, but is not expanded.
W.G. Bugg et al. / Clinical Radiology 69 (2014) 619e623
Figure 2 Small vessel grade 4 EMVI (arrow) on coronal oblique T2weighted MRI. The involved vein runs perpendicular to the rectal lumen and is expanded by intermediate signal tumour.
involved. A small vessel is defined as a perforating vein that runs perpendicular to the rectal lumen (Figs 1 and 2). A medium vessel is defined as an un-named vein that runs parallel to the rectal lumen (Fig 3). A large vessel is defined as involvement of a named vein, which in the context of this study was exclusively the superior rectal vein (Fig 4). The follow-up staging CT, obtained 1 year after the initial diagnosis, was assessed for evidence of metachronous metastases. If present, the site was recorded. Statistical analysis with chi-squared and Fisher’s exact tests were performed using R (www.r-project.org/).
Results Within the present cohort, there were 53 cases (26.2%) of MRI-detected EMVI-positive rectal carcinoma (Table 1). It is of note that grade 3 MRI-detected EMVI only occurred in
621
Figure 4 Large vessel grade 4 EMVI of the superior rectal vein on sagittal T2-weighted MRI. The involved vein is of intermediate signal, grossly expanded, and has an irregular contour.
small vessels. Grade 4 MRI-detected EMVI was only seen in medium and large vessels (Table 1). At 1 year follow-up with CT a total of 23 patients (11$4%) had developed metachronous metastases (Table 2). Of those patients with EMVI-positive rectal carcinoma, 24.5% (13/53) had developed metastases at 1 year follow-up. Of those without EMVI, 6.7% (10/149) had developed metastases at 1 year follow-up. Metastatic disease was present in the liver, lungs, or both (Table 3). For patients with rectal carcinoma who do not have synchronous metastases at the time of diagnosis, there was a significant difference in the incidence of metachronous metastases between those patients with and those without MRI-detected EMVI (Table 3, c2 ¼ 12.29, p < 0$001). In the presence of MRI-detected EMVI at initial staging, there was a 3.7 times increased relative risk of developing metachronous metastases within 1 year of diagnosis. All grades and vessel sizes of MRI-detected EMVI were associated with metachronous metastases at 1 year followup. The incidence of metachronous metastatic disease increased with the increasing severity of EMVI (Table 4; Fig 5). Statistical analysis with Fisher’s exact test reveals that these results were very unlikely to have occurred by chance (p ¼ 0$001).
Discussion The incidence of MRI-detected EMVI-positive rectal carcinoma found in the present study was 26.2% (53/202). This is Table 1 EMVI-positive rectal carcinoma cases categorized by disease grade and vessel size involved.
Figure 3 Medium vessel grade 4 EMVI (arrow) on coronal oblique T2-weighted MRI. The involved vein runs parallel to the rectal lumen. It has an irregular contour and is expanded by tumour of intermediate signal.
EMVI
Small
Medium
Large
Total
Grade 3 Grade 4 Total
23 13 36
0 7 7
0 10 10
23 30 53
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W.G. Bugg et al. / Clinical Radiology 69 (2014) 619e623
Table 2 Cases (%) of metachronous metastatic disease at 1 year related to the presence or absence of extramural venous invasion (EMVI) in rectal carcinoma. EMVI
Metastases
No metastases
Total
Positive Negative Total
13 (6$4) 10 (5$0) 23 (11$4)
40 (19$8) 139 (68$8) 179 (88$6)
53 (26$2) 149 (73$8) 202 (100)
Table 3 Relationship of the site of metachronous metastatic disease at 1 year followup to the presence or absence of extramural venous invasion (EMVI) in rectal carcinoma. Site
EMVI positive
EMVI negative
Total
Liver Lung Liver and lung Total
4 5 4 13
1 7 2 10
5 12 6 23
consistent with previously reported values in the literature. Previous MRI studies have reported the incidence of EMVI as 15.3%1 and 39.4%.16 Histological studies have reported a range of incidences of EMVI between 26.5% and 36%.1,5,8,16 The incidence of venous invasion, both intra and extramural, has been reported as being between 11% and 52%.5,8,17 The results of the present study demonstrate that there is a significant difference in the incidence of metastatic disease at 1 year follow-up between those with and without MRI-detected EMVI in rectal carcinoma. Patients with MRIdetected EMVI-positive rectal carcinoma, in the absence of synchronous metastases, had a 3.7 times increased relative risk of developing metachronous metastatic disease within 1 year of diagnosis, when compared to those with EMVI negative disease. The present results indicate that there was an association between MRI-detected EMVI and the increased risk of developing early metastatic disease. EMVI status at initial MRI staging may, therefore, be a potentially useful predictor of prognosis. It may also be possible to stratify this prognosis further through the use of the MRI grading system described. In the present study an attempt was made to assess the severity of MRI-detected EMVI using two characteristics, grade and vessel size. All grades of MRI-detected EMVI were associated with an increased incidence of metachronous metastatic disease when compared to EMVI-negative rectal tumours. As the severity of MRI-detected EMVI increased, the incidence of metachronous metastases also increased. This supports the hypothesis that tumour embolization into the portal circulation is more likely to occur in the presence of EMVI.
When planning the most appropriate treatment strategy for rectal tumours assessment of the circumferential resection margin (CRM) with MRI is critical.1,18 This is particularly true for T3 M0 (i.e., no synchronous metastatic disease) rectal tumours, which are treated with curative intent. Rectal tumours of stage T3a and T3b, which do not involve the CRM, are commonly treated with primary resection via a total mesorectal excision.19 Rectal tumours of stage T3c and above that may involve the CRM or place it at risk of invasion (defined as tumour within 1 mm of the CRM1) are commonly treated with neoadjuvant chemoradiotherapy.19 This acts to locally downstage the rectal tumour prior to a delayed surgical resection. Should clear resection margins be achieved, adjuvant chemotherapy may be offered, based on the histological characteristics of the resected tumour. Interval follow-up with CT will then begin. Currently, the presence or absence of MRI-detected EMVI does not directly influence preoperative treatment regimens. Neoadjuvant chemoradiotherapy acts to downstage rectal tumours by reducing the depth of tumour invasion.20 The dose of chemotherapy given radiosensitizes the rectal tumour, but is not sufficient to have a systemic effect.21 Neoadjuvant chemoradiotherapy has been shown to reduce local tumour recurrence rates, but has no effect on distant metastases,21 and has little effect on overall survival.22 Complete eradication of malignant cells from the primary rectal tumour may be achieved with neoadjuvant chemoradiotherapy.20 If no viable tumour cells are found within the rectal veins of a resected specimen, the tumour will be classified as EMVI negative. This histological assessment may not fully evaluate the patient’s risk of developing metachronous distant metastases, particularly in those with MRI-detected EMVI on initial staging. In this situation, any micrometastases present at the time of initial diagnosis will remain untreated. In addition, adjuvant chemotherapy may not be
Table 4 Incidence (%) of metachronous metastatic disease at 1 year follow-up related to the severity of EMVI-positive rectal carcinoma. EMVI
Negative
Grade 3 Small
Grade 4 Small
Grade 4 Medium
Grade 4 Large
Total Metastases
149 10 (6$7)
23 3 (13$0)
13 3 (23$1)
7 2 (28$6)
10 5 (50$0)
Figure 5 Histogram demonstrating the increasing incidence of metachronous metastases with increasing severity of MRI-detected EMVI.
W.G. Bugg et al. / Clinical Radiology 69 (2014) 619e623
offered, as this decision is based on the histological staging and not the result of the initial staging MRI. The hypothesis that undiagnosed micrometastases may exist at the time of initial staging of EMVI-positive rectal tumours14,15 is impossible to prove, due to the limitations of current imaging techniques. However, the present results indicate an association between MRI-detected EMVI and an increased risk of developing metachronous metastases within 1 year of diagnosis. The growth of undiagnosed and untreated micrometastases may be the underlying cause. In the presence of MRI-detected EMVI, it is, therefore, reasonable to consider alternative management pathways with the aim of increasing disease-free survival rates. It has been shown that gadoxetic-acid-enhanced MRI at 3 T is significantly more sensitive than 64-row multidetector CT for the detection of small (10 mm) hepatic metastases.23 In those patients with EMVI-positive rectal tumours, early additional staging with MRI could be considered. However, this approach would not alter disease-free survival rates. Rather, it would only allow earlier treatment of detectable metastatic disease. Neoadjuvant chemotherapy, given at a full systemic dose, could have the potential to treat micrometastases before they can progress to more advanced and detectable metastases.22 The present results suggest that the presence of EMVI at initial staging MRI could be used to indicate which patients may benefit from such a treatment strategy. This concept is currently being tested by the UK-based BACCHUS trial in patients with resectable tumours (CRM clear). This retrospective study has a number of limitations. The inclusion criteria may have applied a selection bias if the sample did not represent all patients who did not meet these criteria, either because they did not have an MRI for initial staging or because they were lost to CT follow-up at 1 year. Although the observers were blinded to outcomes, it would not have been possible to blind them to other imaging features of the rectal cancer, and it is conceivable that this might have influenced reported findings. Consensus reporting may have also introduced a reporting bias. The Tstage of the rectal tumour was not recorded or correlated to EMVI status in the present study, as this characteristic is more directly linked to the incidence of local disease recurrence. The number of cases included in the present study was sufficient for the use of chi-square statistics to test the null hypothesis. However, when individual grades of EMVI were considered for subset analysis, the numbers of patients in some of the subsets were less than five, requiring analysis using Fisher’s exact test. Although this still demonstrated a statistically significant association between EMVI grade and outcome, the numbers are too small to assign relative risks to each grade. The results of the present study suggest that MRIdetected EMVI is associated with an increased risk of developing metachronous metastases within 1 year of diagnosis. The presence or absence of MRI-detected EMVI is part of the standard reporting criteria for the initial staging of rectal carcinoma. Therefore, this information is available preoperatively for multidisciplinary team (MDT) discussion and could be used to guide alternative treatment strategies.
623
References 1. Brown G, Radcliffe AG, Newcombe RG, et al. Preoperative assessment of prognostic factors in rectal cancer using high-resolution magnetic resonance imaging. Br J Surg 2003;90:355e64. 2. MERCURY Study Group. Diagnostic accuracy of preoperative magnetic resonance imaging in predicting curative resection of rectal cancer: prospective observational study. BMJ 2006;333:779. 3. MERCURY Study Group. Extramural depth of tumour invasion at thinsection MR in patients with rectal cancer: results of the MERCURY study. Radiology 2007;243:132e9. 4. Taylor F, Swift R, Blomqvist L, et al. A systemic approach to the interpretation of preoperative staging MRI for rectal cancer. AJR Am J Roentgenol 2008;191:1827e35. 5. Talbot IC, Ritchie S, Leighton MH, et al. Spread of rectal cancer within veins. Histologic features and clinical significance. Am J Surg 1981;141:15e7. 6. Sunderland D. The significance of vein invasion by cancer of the rectum and sigmoid: a microscopic study of 210 cases. Cancer 1949;2:429e37. 7. Smith NJ, Shihab O, Arnaout A, et al. MRI for detection of extramural vascular invasion in rectal cancer. AJR Am J Roentgenol 2008;191:1517e22. 8. Krasna MJ, Flancbaum L, Cody RP, et al. Vascular and neural invasion in colorectal carcinoma. Incidence and prognostic significance. Cancer 1988;61:1018e23. 9. Talbot IC, Ritchie S, Leighton MH, et al. The clinical significance of invasion of veins in cancer of the rectum. Br J Surg 1980;67:439e42. 10. Shirouzu K, Isomoto H, Kakegawa T, et al. A prospective clinicopathologic study of venous invasion in colorectal cancer. Am J Surg 1991;162:216e22. 11. Horn A, Dahl O, Morild I. Venous and neural invasion as predictors of recurrence in rectal adenocarcinoma. Dis Colon Rectum 1991;34:798e804. 12. Bokey EL, Chapuis PH, Dent OF, et al. Factors affecting survival after excision of the rectum for cancer: a multivariate analysis. Dis Colon Rectum 1997;40:3e10. 13. Hunter CJ, Garant A, Vuong T, et al. Adverse features on rectal MRI identify a high-risk group that may benefit from more intensive preoperative staging and treatment. Ann Surg Oncol 2012;19:1199e205. 14. Ouchi K, Sugawara T, Ono H, et al. Histologic features and clinical significance of venous invasion in colorectal carcinoma with hepatic metastasis. Cancer 1996;78:2313e7. 15. Brown G. Thin section MRI in multidisciplinary pre-operative decision making for patients with rectal cancer. Br J Radiol 2005;78:S117e27. 16. Smith NJ, Barbachano Y, Norman AR, et al. Prognostic significance of magnetic resonance imaging-detected extramural vascular invasion in rectal cancer. Br J Surg 2008;95:229e36. 17. Dukes C, Bussey HJ. The spread of rectal cancer and its effect on prognosis. Br J Cancer 1958;12:309e20. 18. Brown G, Kirkham A, Williams GT, et al. High-resolution MRI of the anatomy important in total mesorectal excision of the rectum. AJR Am J Roentgenol 2004;182:431e9. 19. Schmoll HJ, Van Cutsem E, Stein A, et al. ESMO consensus guidelines for management of patients with colon and rectal cancer. A personalized approach to clinical decision making. Ann Oncol 2012;23:2479e516. 20. Rodel C, Martus P, Papadoupolos T, et al. Prognostic significance of tumour regression after chemoradiotherapy for rectal cancer. J Clin Oncol 2005;23:8688e96. 21. Chau I, Brown G, Cunningham D, et al. Neoadjuvant capecitabine and oxaliplatin followed by synchronous chemoradiation and total mesorectal excision in magnetic resonance imaging-defined poor-risk rectal cancer. J Clin Oncol 2006;24:668e74. 22. Glynne-Jones R, Anyamene N, Moran B, et al. Neoadjuvant chemotherapy in MRI-staged high-risk rectal cancer in addition to or as an alternative to preoperative chemoradiation. Ann Oncol 2012;23:2517e26. 23. Scharitzer M, Ba-Ssalamah A, Ringl H, et al. Preoperative evaluation of colorectal liver metastases: comparison between gadoxetic acidenhanced 3.0 T MRI and contrast enhanced MDCT with histopathological correlation. Eur Radiol 2013;23:2187e96.
Contents lists available at ScienceDirect
Clinical Radiology journal homepage: www.clinicalradiologyonline.net
The prognostic significance of MRI-detected extramural venous invasion in rectal carcinoma W.G. Bugg a, A.K. Andreou a, D. Biswas b, A.P. Toms a, S.M. Williams a, * a b
Department of Radiology, Norfolk and Norwich University Hospital NHS Foundation Trust, Norwich, UK Department of Oncology, Norfolk and Norwich University Hospital NHS Foundation Trust, Norwich, UK
art icl e i nformat ion Article history: Received 30 October 2013 Received in revised form 6 January 2014 Accepted 14 January 2014
AIM: To assess whether there is a significant difference in the incidence of patients with metastases of rectal carcinoma at 1 year follow-up between magnetic resonance imaging (MRI)-detected extramural venous invasion (EMVI) and those without. MATERIALS AND METHODS: A search of our institution’s cancer registry revealed 788 patients with rectal carcinoma between January 2007 and April 2012. Those who were initially staged using MRI and computed tomography (CT) chest/abdomen/pelvis, and followed-up with a CT chest/abdomen/pelvis examination at 1 year were included in this retrospective study. Patients with synchronous metastases were excluded, leaving a cohort of 202 cases. Two consultant radiologists reviewed all MRI images and gave a consensus opinion regarding EMVI grade and vessel size involved. All CT images were reviewed for metastases. Results were analysed using chi-squared and Fisher’s exact tests. RESULTS: There were 53 cases (26.2%) of EMVI-positive rectal carcinoma. Of the patients with EMVI, 24.5% developed metastases at 1 year follow-up, compared to 6.7% of those without. There is a significant difference in prognosis between those patients with and those without MRI-detected EMVI (c2 ¼ 12.29, p < 0$001). Those with EMVI have a 3.7 times increased relative risk of developing metachronous metastases within 1 year of diagnosis. CONCLUSION: MRI-detected EMVI-positive rectal carcinomas are associated with an increased risk of metachronous metastases within 1 year of diagnosis. Currently, EMVI status does not directly influence the initial management of rectal carcinoma. This available and potentially prognostic feature could be used to guide treatment pathways to increase diseasefree survival. Ó 2014 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
Introduction The local staging of rectal carcinoma with highresolution magnetic resonance imaging (MRI) has been shown to be accurate1 and reproducible.2 It enables preoperative planning of primary tumour resection or may indicate the need for neoadjuvant therapy. The aim of this
* Guarantor and correspondent: S.M. Williams, Norwich Radiology Academy, Cotman Centre, Colney Lane, Norwich, Norfolk NR4 7UB, UK. Tel.: þ44 01603 286143; fax: þ44 01603 286146. E-mail address: [email protected] (S.M. Williams).
detailed preoperative staging is to facilitate long-term disease-free survival. A systematic approach for the reporting of local-staging MRI for rectal cancer has been developed as a result of the work carried out by the MERCURY Study Group.3,4 This highlights the most important staging characteristics, including extramural venous invasion (EMVI), which is recognized as a poor prognostic feature.1 EMVI is defined histologically as the presence of tumour cells beyond the muscularis propria in an endotheliumlined vessel.4 It is possible to diagnose both intra- and extramural venous invasion associated with rectal carcinoma during histological examination of a surgical
0009-9260/$ e see front matter Ó 2014 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.crad.2014.01.010
620
W.G. Bugg et al. / Clinical Radiology 69 (2014) 619e623
specimen.5 However, MRI can only demonstrate EMVI.1 EMVI will only be present in locally advanced rectal tumours, of stage T3 or T4.6,7 The diagnostic capabilities of MRI with respect to EMVI are, therefore, limited to the more severe end of the disease spectrum. It is accepted that venous invasion by colorectal cancer allows tumour cells to embolize, via the portal circulation, resulting in distant metastases through haematogenous spread.5 The liver is most commonly affected.8,9 Histologically detected venous invasion of rectal carcinoma is associated with a higher incidence of metachronous local10 and distant10,11 metastases. It is also associated with poorer overall survival rates.12 The presence of MRI-detected EMVI is a poor prognostic feature of rectal carcinoma and is associated with an increased risk of synchronous metastases.13 To the authors’ knowledge, the association between MRI-detected EMVI and the development of metachronous metastases has not been described in the literature. It is suggested that the increased incidence of metachronous metastases associated with EMVI-positive rectal cancers is, in some part, due to the presence of micrometastases.14,15 These are impossible to diagnose with initial staging computed tomography (CT). The authors’ hypothesise that micrometastases, if present at the time of initial staging, should progress to detectable metastases at an early stage if left untreated. The aim of the present study was to assess whether there is a significant difference in the incidence of patients with metastases at 1 year follow-up between those with MRIdetected EMVI and those without.
Materials and methods Institutional ethics committee approval for this retrospective study was not required but the study was performed in accordance with the principles of the Declaration of Helsinki. A search of our single-hospital electronic cancer registry (Somerset Informatics Service) revealed 788 patients with a diagnosis of primary rectal carcinoma recorded between January 2007 and April 2012. Those patients who were initially investigated via MRI of the rectum and a CT examination of the chest, abdomen, and pelvis for both local and distant staging, and also followed up with a CT examination of the chest, abdomen, and pelvis at 1 year post-diagnosis were included in the study. Patients who were found to have synchronous metastases at initial staging were excluded from the study. There were 229 cases that met the study inclusion criteria; of these, 27 cases had synchronous metastases and were excluded. A cohort of 202 cases remained (male ¼ 123, female ¼ 79; median age 66 years, range 32e84). For all cases that met the inclusion and exclusion criteria, the initial staging MRI images of the rectum were reviewed on a high-resolution picture archiving and communication system (Fujifilm Synapse, Fuji Photo Film Co. Ltd, Tokyo, Japan) workstation (Eizo Radiforce RX320 monitors, Eizo Corporation, Hakusan, Ishikawa, Japan) by two consultant
radiologists with a subspecialty interest in colorectal imaging (individual experience of 15 and 5 years, respectively). The MRI examinations were carried out using a 1.5 T Siemens Avanto (Siemens Medical Systems, Erlangen, Germany) system, using a six-channel body matrix coil anteriorly and a six-channel spine matrix coil posteriorly, which combine to create a 12-channel configuration. The standard imaging sequences obtained were axial T1-weighted turbo spin-echo [13 ms echo time (TE), 579 ms repetition time (TR), 320 256 matrix, 34 37 cm field of view (FOV), 6 mm section thickness, 8 mm spacing] and axial T2weighted turbo spin-echo (96 ms TE, 4960 ms TR, 320 256 matrix, 34 37 cm FOV, 6 mm section thickness, 8 mm spacing) of the pelvis. High-resolution sagittal T2weighted turbo spin-echo (97 ms TE, 4692 ms TR, 288 384 matrix, 23 25.1 cm FOV, 4 mm section thickness, 5 mm spacing), coronal oblique T2-weighted turbo spin-echo (81 ms TE, 4670 ms TR, 256 256 matrix, 22 24 cm FOV, 3 mm section thickness, 3.6 mm spacing) and axial oblique T2-weighted turbo spin-echo (81 ms TE, 5610 ms TR, 256 256 matrix, 22 24 cm FOV, 3 mm section thickness, 3.6 mm spacing) images were obtained of the rectal tumour. The reporters were blind to the study history and original report. The EMVI status of each case was assessed only. All cases of EMVI-positive disease were graded16 and the size of vessel involved was recorded. A consensus opinion was recorded for each study. The EMVI grading score used in this study was taken from the system proposed by Smith et al.16 Grades 0e2 are effectively EMVI-negative disease and were recorded as such, without distinction. Grades 3 and 4 correspond to EMVI-positive disease. Grade 3 EMVI describes tumour within a vein that does not alter its contour and may only slightly expand the vessel (Fig 1). Grade 4 EMVI describes an irregular expanded vein implying vessel wall invasion (Fig 4). The distance by which the EMVI had extended from the rectal tumour was assessed with respect to the size of vessel
Figure 1 Small vessel grade 3 EMVI (arrow) on coronal oblique T2weighted MRI. The involved vein is of intermediate signal (similar to the tumour and with no flow void), runs perpendicular to the rectal lumen, but is not expanded.
W.G. Bugg et al. / Clinical Radiology 69 (2014) 619e623
Figure 2 Small vessel grade 4 EMVI (arrow) on coronal oblique T2weighted MRI. The involved vein runs perpendicular to the rectal lumen and is expanded by intermediate signal tumour.
involved. A small vessel is defined as a perforating vein that runs perpendicular to the rectal lumen (Figs 1 and 2). A medium vessel is defined as an un-named vein that runs parallel to the rectal lumen (Fig 3). A large vessel is defined as involvement of a named vein, which in the context of this study was exclusively the superior rectal vein (Fig 4). The follow-up staging CT, obtained 1 year after the initial diagnosis, was assessed for evidence of metachronous metastases. If present, the site was recorded. Statistical analysis with chi-squared and Fisher’s exact tests were performed using R (www.r-project.org/).
Results Within the present cohort, there were 53 cases (26.2%) of MRI-detected EMVI-positive rectal carcinoma (Table 1). It is of note that grade 3 MRI-detected EMVI only occurred in
621
Figure 4 Large vessel grade 4 EMVI of the superior rectal vein on sagittal T2-weighted MRI. The involved vein is of intermediate signal, grossly expanded, and has an irregular contour.
small vessels. Grade 4 MRI-detected EMVI was only seen in medium and large vessels (Table 1). At 1 year follow-up with CT a total of 23 patients (11$4%) had developed metachronous metastases (Table 2). Of those patients with EMVI-positive rectal carcinoma, 24.5% (13/53) had developed metastases at 1 year follow-up. Of those without EMVI, 6.7% (10/149) had developed metastases at 1 year follow-up. Metastatic disease was present in the liver, lungs, or both (Table 3). For patients with rectal carcinoma who do not have synchronous metastases at the time of diagnosis, there was a significant difference in the incidence of metachronous metastases between those patients with and those without MRI-detected EMVI (Table 3, c2 ¼ 12.29, p < 0$001). In the presence of MRI-detected EMVI at initial staging, there was a 3.7 times increased relative risk of developing metachronous metastases within 1 year of diagnosis. All grades and vessel sizes of MRI-detected EMVI were associated with metachronous metastases at 1 year followup. The incidence of metachronous metastatic disease increased with the increasing severity of EMVI (Table 4; Fig 5). Statistical analysis with Fisher’s exact test reveals that these results were very unlikely to have occurred by chance (p ¼ 0$001).
Discussion The incidence of MRI-detected EMVI-positive rectal carcinoma found in the present study was 26.2% (53/202). This is Table 1 EMVI-positive rectal carcinoma cases categorized by disease grade and vessel size involved.
Figure 3 Medium vessel grade 4 EMVI (arrow) on coronal oblique T2-weighted MRI. The involved vein runs parallel to the rectal lumen. It has an irregular contour and is expanded by tumour of intermediate signal.
EMVI
Small
Medium
Large
Total
Grade 3 Grade 4 Total
23 13 36
0 7 7
0 10 10
23 30 53
622
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Table 2 Cases (%) of metachronous metastatic disease at 1 year related to the presence or absence of extramural venous invasion (EMVI) in rectal carcinoma. EMVI
Metastases
No metastases
Total
Positive Negative Total
13 (6$4) 10 (5$0) 23 (11$4)
40 (19$8) 139 (68$8) 179 (88$6)
53 (26$2) 149 (73$8) 202 (100)
Table 3 Relationship of the site of metachronous metastatic disease at 1 year followup to the presence or absence of extramural venous invasion (EMVI) in rectal carcinoma. Site
EMVI positive
EMVI negative
Total
Liver Lung Liver and lung Total
4 5 4 13
1 7 2 10
5 12 6 23
consistent with previously reported values in the literature. Previous MRI studies have reported the incidence of EMVI as 15.3%1 and 39.4%.16 Histological studies have reported a range of incidences of EMVI between 26.5% and 36%.1,5,8,16 The incidence of venous invasion, both intra and extramural, has been reported as being between 11% and 52%.5,8,17 The results of the present study demonstrate that there is a significant difference in the incidence of metastatic disease at 1 year follow-up between those with and without MRI-detected EMVI in rectal carcinoma. Patients with MRIdetected EMVI-positive rectal carcinoma, in the absence of synchronous metastases, had a 3.7 times increased relative risk of developing metachronous metastatic disease within 1 year of diagnosis, when compared to those with EMVI negative disease. The present results indicate that there was an association between MRI-detected EMVI and the increased risk of developing early metastatic disease. EMVI status at initial MRI staging may, therefore, be a potentially useful predictor of prognosis. It may also be possible to stratify this prognosis further through the use of the MRI grading system described. In the present study an attempt was made to assess the severity of MRI-detected EMVI using two characteristics, grade and vessel size. All grades of MRI-detected EMVI were associated with an increased incidence of metachronous metastatic disease when compared to EMVI-negative rectal tumours. As the severity of MRI-detected EMVI increased, the incidence of metachronous metastases also increased. This supports the hypothesis that tumour embolization into the portal circulation is more likely to occur in the presence of EMVI.
When planning the most appropriate treatment strategy for rectal tumours assessment of the circumferential resection margin (CRM) with MRI is critical.1,18 This is particularly true for T3 M0 (i.e., no synchronous metastatic disease) rectal tumours, which are treated with curative intent. Rectal tumours of stage T3a and T3b, which do not involve the CRM, are commonly treated with primary resection via a total mesorectal excision.19 Rectal tumours of stage T3c and above that may involve the CRM or place it at risk of invasion (defined as tumour within 1 mm of the CRM1) are commonly treated with neoadjuvant chemoradiotherapy.19 This acts to locally downstage the rectal tumour prior to a delayed surgical resection. Should clear resection margins be achieved, adjuvant chemotherapy may be offered, based on the histological characteristics of the resected tumour. Interval follow-up with CT will then begin. Currently, the presence or absence of MRI-detected EMVI does not directly influence preoperative treatment regimens. Neoadjuvant chemoradiotherapy acts to downstage rectal tumours by reducing the depth of tumour invasion.20 The dose of chemotherapy given radiosensitizes the rectal tumour, but is not sufficient to have a systemic effect.21 Neoadjuvant chemoradiotherapy has been shown to reduce local tumour recurrence rates, but has no effect on distant metastases,21 and has little effect on overall survival.22 Complete eradication of malignant cells from the primary rectal tumour may be achieved with neoadjuvant chemoradiotherapy.20 If no viable tumour cells are found within the rectal veins of a resected specimen, the tumour will be classified as EMVI negative. This histological assessment may not fully evaluate the patient’s risk of developing metachronous distant metastases, particularly in those with MRI-detected EMVI on initial staging. In this situation, any micrometastases present at the time of initial diagnosis will remain untreated. In addition, adjuvant chemotherapy may not be
Table 4 Incidence (%) of metachronous metastatic disease at 1 year follow-up related to the severity of EMVI-positive rectal carcinoma. EMVI
Negative
Grade 3 Small
Grade 4 Small
Grade 4 Medium
Grade 4 Large
Total Metastases
149 10 (6$7)
23 3 (13$0)
13 3 (23$1)
7 2 (28$6)
10 5 (50$0)
Figure 5 Histogram demonstrating the increasing incidence of metachronous metastases with increasing severity of MRI-detected EMVI.
W.G. Bugg et al. / Clinical Radiology 69 (2014) 619e623
offered, as this decision is based on the histological staging and not the result of the initial staging MRI. The hypothesis that undiagnosed micrometastases may exist at the time of initial staging of EMVI-positive rectal tumours14,15 is impossible to prove, due to the limitations of current imaging techniques. However, the present results indicate an association between MRI-detected EMVI and an increased risk of developing metachronous metastases within 1 year of diagnosis. The growth of undiagnosed and untreated micrometastases may be the underlying cause. In the presence of MRI-detected EMVI, it is, therefore, reasonable to consider alternative management pathways with the aim of increasing disease-free survival rates. It has been shown that gadoxetic-acid-enhanced MRI at 3 T is significantly more sensitive than 64-row multidetector CT for the detection of small (10 mm) hepatic metastases.23 In those patients with EMVI-positive rectal tumours, early additional staging with MRI could be considered. However, this approach would not alter disease-free survival rates. Rather, it would only allow earlier treatment of detectable metastatic disease. Neoadjuvant chemotherapy, given at a full systemic dose, could have the potential to treat micrometastases before they can progress to more advanced and detectable metastases.22 The present results suggest that the presence of EMVI at initial staging MRI could be used to indicate which patients may benefit from such a treatment strategy. This concept is currently being tested by the UK-based BACCHUS trial in patients with resectable tumours (CRM clear). This retrospective study has a number of limitations. The inclusion criteria may have applied a selection bias if the sample did not represent all patients who did not meet these criteria, either because they did not have an MRI for initial staging or because they were lost to CT follow-up at 1 year. Although the observers were blinded to outcomes, it would not have been possible to blind them to other imaging features of the rectal cancer, and it is conceivable that this might have influenced reported findings. Consensus reporting may have also introduced a reporting bias. The Tstage of the rectal tumour was not recorded or correlated to EMVI status in the present study, as this characteristic is more directly linked to the incidence of local disease recurrence. The number of cases included in the present study was sufficient for the use of chi-square statistics to test the null hypothesis. However, when individual grades of EMVI were considered for subset analysis, the numbers of patients in some of the subsets were less than five, requiring analysis using Fisher’s exact test. Although this still demonstrated a statistically significant association between EMVI grade and outcome, the numbers are too small to assign relative risks to each grade. The results of the present study suggest that MRIdetected EMVI is associated with an increased risk of developing metachronous metastases within 1 year of diagnosis. The presence or absence of MRI-detected EMVI is part of the standard reporting criteria for the initial staging of rectal carcinoma. Therefore, this information is available preoperatively for multidisciplinary team (MDT) discussion and could be used to guide alternative treatment strategies.
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